Abstract
This review highlights several in vivo studies utilizing non-genotoxic and genotoxic chemical carcinogens, and the mechanisms of their high and low dose carcinogenicities with respect to formation of oxidative stress. Here, we survey the examples and discuss possible mechanisms of hormetic effects with cytochrome P450 inducers, such as phenobarbital, α-benzene hexachloride and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane. Epigenetic processes differentially can be affected by agents that impinge on oxidative DNA damage, repair, apoptosis, cell proliferation, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. We further discuss role of oxidative stress focusing on the low dose carcinogenicities of several genotoxic carcinogens such as a hepatocarcinogen contained in seared fish and meat, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, arsenic and its metabolites, and the kidney carcinogen potassium bromate.
Highlights
In aerobic organisms, the balance in production of various oxidants like reactive oxygen and nitrogen species (ROS/RNS), which are invariable components of the aerobic metabolism, and their elimination by intracellular antioxidants of enzymatic nature such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GTPx) and nonenzymatic nature such as radical scavengers like vitamin E, ferritins, different thiols, and others helps to maintain cellular homeostasis and to protect from formation of cellular oxidative stress [1,2,3]
The results demonstrated that short-term exposure to the non-genotoxic chemical, ethyl tert-butyl ether (ETBE) administered to rats by gavage activated constitutive androstane receptor (CAR) and pregnane X receptor (PXR) nuclear receptors in the livers similar to the mechanism possessed by the non-genotoxic chemical carcinogen, PB, and activated peroxisome proliferator receptors (PPARs), leading to conspicuous elevation of 8-OHdG
The results indicated that early elevation of 8-OHdG and cell proliferation via generation of oxidative stress by TMAOV and DMAV contributes to their carcinogenicity in the rat liver and bladder [84]
Summary
The balance in production of various oxidants like reactive oxygen and nitrogen species (ROS/RNS), which are invariable components of the aerobic metabolism, and their elimination by intracellular antioxidants of enzymatic nature such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GTPx) and nonenzymatic nature such as radical scavengers like vitamin E, ferritins, different thiols, and others helps to maintain cellular homeostasis and to protect from formation of cellular oxidative stress [1,2,3]. PPARs activation has been linked with liver tumor formation and the mechanisms include induction of sustained oxidative stress, enhanced cell replication, promotion of preneoplastic lesions, and inhibition of apoptosis [19]. ROS oxidize lipid and protein molecules, generating intermediates, which can react with DNA and form adducts, or directly attack the DNA, damaging the bases and deoxyribose residues and producing single strand breaks. It was accepted that the indirect nature of the mechanisms involved means that prolonged exposure to high levels of chemicals is necessary for the production of tumors [42] With such non-genotoxic carcinogens, theoretically cancer would not occur at exposure below a threshold at which the relevant cellular effect is not operative. Non-genotoxic carcinogens can elicit a variety of changes contributing to cellular carcinogenesis
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